Serotonin (5-HT) is a key neurotransmitter and signaling molecule in the gut. 5-HT release from enterochromaffin cells residing within the intestinal mucosa results in transduction of luminal stimuli initiating peristaltic, secretory and nociceptive reflexes. The serotonin-selective reuptake transporter (SERT), which is expressed on intestinal enterocytes, terminates the actions of 5-HT by removing it from the interstitial space. Disruption of these actions could lead to altered serotonergic signaling and potential gastrointestinal dysfunction. The role of the 5-HT in IBS remains unclear, but our recent data suggest distinct changes of 5- HT availability exist in individuals with this disorder. We have demonstrated that individuals with IBS have decreased levels of SERT while maintaining levels of 5-HT release comparable to those of healthy controls. It is possible that diminished uptake could allow 5-HT to persist within the interstitium longer than normal, causing overstimulation of the serotonergic reflexes noted above. The overall hypothesis to be tested by these proposed studies is that intestinal 5-HT availability is increased in IBS due to decreased expression of SERT, and that resultant changes in 5-HT signaling contribute to altered gut function in IBS.